Non-insulin-dependent diabetes mellitus (NIDDM) is highly prevalent in the U.S. population, reaching 10-20% in people 50 years and older. This incidence is higher among certain ethnic groups (Harris, M. I., Diabetes Care 16:642-652 (1993)). The condition is associated in the early phase with obesity, especially visceral and middle obesity. The progression from obesity to non-insulin dependent diabetes is characterized by the gradual development of insulin resistance occurring at least 4-7 years before clinical diagnosis of NIDDM (Harris, M. I., Diabetes Care 16:642-652 (1993); Harris, M. I., et al., Diabetes Care 15:815-819 (1992)). Insulin resistance is defined as the decrease in the biological action of insulin on the classical insulin sensitive tissues, namely muscle and liver leading to a reduced uptake and utilization of glucose from the bloodstream. In response to the reduced actions of insulin, the mounting plasma glucose induces the pancreas to put out more insulin leading to a higher basal circulating levels of the hormone in the interprandial state. Thus, insulin resistance often presents as hyperinsulinemia (Bonner, G., J Cardiovascular Pharmacology 24(Suppl. 2):S39-S49) (1994)). Initially, the higher circulating levels of insulin compensate for the reduced sensitivity to the hormone. As the pancreas decompensates and becomes unable to keep up with the demand, a fragile metabolic state of impaired glucose tolerance results. In this state, the organism is unable to handle a high influx of glucose into the bloodstream, for example after a meal or to a glucose challenge. This typically demonstrated by the slow rate in normalizing plasma glucose after a meal compared to normal individuals. It is at this point that non-insulin-dependent diabetes is usually diagnosed.
The period of some 5-10 years proceeding the development of impaired glucose tolerance is thus associated with a number of hormonal imbalances, e.g., increased basal insulin and glucagon production, elevated adrenal corticoid secretion (Bjornstop, P., In: Current Topics in Diabetes Research, eds. Belfore, F., Bergman, R N, and Molinath, G M, Front Diabetes, Basel, Karger, 12:182-192 (1993)), giving rise to the characteristic enlargement of visceral fat mass, hypertension, insulin resistance, and hyperlipidemia.
The cluster of these metabolic abnormalities has been referred to as “Syndrome X”, “Metabolic Syndrome”, “insulin resistant syndrome”, or “Plurimetabolic Syndrome” (Reaven, G. M., Diabetes 37:1595-1607 (1988); Branchi, R., et al., Diab. Nutr. Metab. 7:43-51 (1994)). The condition was also shown to be associated with an increased risk for atherosclerosis, and coronary heart disease (reviewed in Wajchenberg, B. L., et al., Diabetes/Metabolism Reviews 10:19-29 (1994); Reaven, G. M., J. Int. Med. 236(Suppl. 736) :134-22 (1994); Woods, J. E., Ann. Intern. Med. 13:81-90 (1939); Modan, A., et al., J. Clin. Invest. 75:809-817 (1985)). Although the causal relationship between the various metabolic components remains to be confirmed (Donahue, R. P., The Endocrinologist 4:112-116 (1994); Fontbonne, A., Circulation 88(4 Pt.1):1952-1953 (1993); Jarrett, R. J., Diabetologia 37:945-947 (1994); Reaven, G. M., et al., Diabetologia 37:948-952 (1994); McCarty, M. F., Medical Hypothesis 42:226-236 (1994); Feskens, E. J. M., et al., Arteriosclerosis and Thrombosis 14:1641-1647 (1994)), insulin resistance appears to play an important role (Requen, G. M., et al., N. Eng. J. Med. 334:374-381 (1996); Despres, J-P., et al., N. Engl. J. Med. 334:952-957 (1996); Wajchenberg, B. L., et al., Diabetes/Metabolism Rev. 10:19-29 (1994)). There are no approved or confirmed effective treatments for the “insulin resistant syndrome” or “Syndrome X”. Emerging data suggest that a number of therapies currently approved for the management of NIDDM may alleviate insulin resistance, e.g., Metformin (DeFronzo, R. A., et al., N. Eng. J. Med. 333:541-549 (1995)), Troghtazone (Kumar, S., et al., Diabetologia 39:701-709 (1996).
There is preliminary evidence in humans that acute infusion of somatostatin in obese hyperinsulinemic hypertensive patients resulted in a transient decrease in mean arterial blood pressure (Carretta, R., et al., J. Hypertension 7(suppl 6) :S196-S197 (1989)). Although this study pointed to a potential role of somatostatin in the management of hypertension associated with obesity, hypertension is only one of the clinical outcomes in the constellation of abnormalities associated with Syndrome X (Wajchenberg, B. L., et al., Diabetes/Metabolism Rev. 10:19-29 (1994)). A role of insulin is also implicated in the study. The involvement of insulin remains controversial as an acute increase in plasma insulin after a meal is typically associated with a reduction in blood pressure. Also, prolonged maintenance of hyperinsulinemia in animals does not raise blood pressure (McCarty, M. F., Medical Hypothesis, 1994, 42, 226-236). Also, epidemiologic studies have not yielded a clear-cut association between hyperinsulinemia and the risk for coronary heart disease (Jarrett, R. S., Diabetologia 37:945-947 (1994); Giuliano, D., et al., J. Endocrinol. Invest. 17:391-396 (1991); Feskens, E. J. M., Arterioscler. Thromb. 14:1641-1647 (1994); Ohmori, S., et al., J. Hypertension 12:1191-1197 (1994); Reaven, G. M., Diabetologia 37:948-592 (1994)).
The effect of somatostatin is mediated by a family of five somatostatin receptor isotypes. The current invention identifies a salient role of somatostatin agonists (e.g., somatostatin type-5 agonists) for the management of insulin resistance and Syndrome X as well as the normalization of metabolic changes that could mitigate development of disorders associated with Syndrome X, i.e. hyperlipidemia, insulin resistance and hyperinsulinemia.